Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors accounting for >150,000 deaths worldwide each year. Most patients present with inoperable, metastatic disease for which there are no effective therapies. Thus, research is urgently needed to determine how PDACs progress in order to design better therapies. We are studying the molecular pathways that lead to tumor progression in PDAC. Our focus is the HMGA2 oncogene, which encodes the HMGA2 chromatin remodeling protein. My laboratory discovered that HMGA2 functions as a potent oncogene in cultured cells and inhibiting HMGA2 expression blocks transformation phenotypes. Recently published studies from our group demonstrate that HMGA2 is overexpressed in 44% of primary, human PDACs, with highest levels in invasive, metastatic tumors, but no expression in precursor lesions or normal pancreas. Moreover, our recent study found that HMGA2 protein levels are positively correlated with poor differentiation status and lymph node metastases. These findings strongly suggest that HMGA2 promotes tumor progression in PDAC, although the molecular mechanisms through which HMGA2 functions are unclear. Emerging evidence indicate that microRNAs (miRNAs) play a critical role in tumor progression and maintenance of a poorly differentiated state. miRNAs are a highly conserved family of small, non-protein-coding RNAs that regulate the stability or translation efficiency of complementary target mRNAs. A recent study from the Maitra & Mendell laboratories identified tumor suppressor microRNAs (TS-miRs) that are down-regulated in cultured cells from aggressive PDACs compared to cells from normal pancreas, suggesting that repression of specific TS-miRs could promote tumorigenesis. Let-7 miRNAs were among the repressed miRNAs and let-7 functions as a TS-miR in diverse tumors. Preliminary evidence also indicates that let-7 represses HMGA2 and other oncogenes. Thus, loss of let-7 in PDAC could lead to up-regulation of oncogenic proteins and tumor progression. Based on these findings, we hypothesize that the let-7-HMGA2 regulatory loop is an important pathway involved in metastatic progression in PDAC. We hypothesize further that replacing let-7 in PDAC will down-regulate oncogenic proteins and block tumor progression. Moreover, we have developed an innovative, in vivo nanovector delivery system that effectively restores let-7 miRNAs in pancreatic cancer cells. Using our unique resources, we now propose to test these hypotheses with the following Specific Aims: 1.) Define the functional significance of the let-7-HMGA2 network in PDAC, 2.) Determine if replacing let-7 TS-miR with an innovative miRNA nanovector delivery system blocks tumorigenesis and metastatic progression in our experimental models of PDAC. Results from these studies will enhance our understanding of the molecular pathways that lead to pancreatic cancer progression and should provide a new paradigm for miRNA therapy in PDAC PUBLIC HEALTH RELEVANCE: There is a dire need for research to identify rational therapies for pancreatic cancer because virtually all patients with this cancer die from disease progression. This year alone, almost 30,000 people in the U.S. will succumb to pancreatic cancer with over 150,000 deaths worldwide. In this grant, we propose studies to identify cellular pathways important in tumor progression in pancreatic cancer with emphasis on novel pathways that could be targeted in therapy.